Association between Serum Thyroid Stimulating Hormone (TSH) and Cancer Recurrence among Adult Patients with Differentiated Thyroid Cancer (DTC): A retrospective cohort study

Differentiated thyroid cancer (DTC) is a common endocrine neoplasm. Initial treatment involves thyroidectomy with or without radioactive iodine (RAI) and usually followed by thyroxine treatment, a synthetic thyroid hormone replacement. Serum Thyroid Stimulating Hormone (TSH), also known as thyrotropin, is monitored to guide thyroxine dosing to maintain thyroid function and to avoid TSH elevation which may stimulate residual tissue and promote DTC recurrence. There is currently limited evidence to guide TSH targets in DTC survivors after initial management. While keeping TSH in the normal reference of 0.5-4 mIU/L is adequate for maintaining normal thyroid function, the American Thyroid Association (ATA) guidelines recommend targeting a TSH in the lower range of <2 mIU/L to reduce recurrence risk. However, there is limited evidence regarding the benefit of targeting TSH in this tighter range, particularly in patients with tumours that have a low-risk of recurrence. This lack of evidence may result in variations in practice, and may expose patients to unnecessary, excess treatment and associated morbidities such as atrial fibrillation, stroke, and non-traumatic fractures with uncertain benefit. In that context, we sought to determine the relationship between exposure to low normal TSH (0.5-2 mIU/L) as compared to high normal TSH (2-4 mIU/L) and disease recurrence in DTC patients who underwent thyroidectomy in Ontario from 2007 to 2018. We also evaluated the association between TSH exposure and non-cancer outcomes of atrial fibrillation, stroke, non-traumatic fractures, and all cause death. This was a retrospective cohort study of surgically treated DTC patients using linked, administrative health databases. Multivariable Cox proportional hazard regression analyses were performed to evaluate the association between serum TSH values and time to recurrence and non-cancer outcomes, with TSH treated as a time-varying exposure. TSH was modeled as a time-updated instantaneous and cumulative exposure, both as a continuous and categorical variable. Disease recurrence was defined as a composite outcome of the first occurrence of repeat surgery or radioactive iodine (RAI) at least 1 year following initial surgical treatment, or DTC specific death. The cohort comprised of 26,336 individuals (78% female), with a median age of 50 years, followed for a median of 5.9 years. There was a modest but significant direct association between increasing TSH and risk of disease recurrence (adjusted cause specific hazard ratio [csHR] 1.001, 95% confidence interval [CI] 1.001-1.001, p<0.0001), after adjustment for relevant covariates. In multivariable, competing risk analysis modeling TSH as a categorical variable, we found that compared with instantaneous exposure to TSH between 0.5-2 mIU/L (referent), exposure to TSH 2-4 mIU/L was associated with a similar risk of disease recurrence (adjusted csHR 1.08, 95% CI 0.89-1.32, p=0.4468). Exposure to TSH outside the normal range (>4 mIU/L) was associated with a significant increase in disease recurrence compared to the referent range of 0.5-2 mIU/L (adjusted csHR 1.53, 95% CI 1.33-1.77, p<0.0001, csHR 3.10, 95% CI 2.59-3.71, p<0.0001, csHR 18.47, 95% CI 16.05-21.26, p<0.0001 for TSH <0.5 mIU/L, >4 - ≤10 mIU/L and >10 mIU/L, respectively). When TSH categories were modeled as cumulative exposure, we found that there was no increase in disease recurrence risk for each additional 3 months of exposure to TSH 2-4 mIU/L compared to the referent range of TSH 0.5-2 mIU/L (adjusted csHR 0.99, 95% CI 0.97-1.02, p=0.5507). In contrast, each additional 3 months of exposure to TSH above the normal range (>4 mIU/L) were associated with a significant 7% increased risk of disease recurrence (adjusted csHR 1.07, 95% CI 1.04-1.09, p<0.0001). Exposure to TSH <0.5 mIU/L or 0.5-2 mIU/L was not associated with a higher rate of atrial fibrillation, strokes, non-traumatic fractures or all cause death compared to TSH 2-4 mIU/L. In conclusion, in this cohort of DTC survivors, there was no benefit of exposure to low-normal TSH between 0.5 and 2 mIU/L compared to high-normal TSH (2-4 mIU//L) on risk of DTC recurrence. Therefore, our results suggest that the TSH target may be safely liberalized up to 4 mIU/L without increased recurrence for DTC survivors. Future studies such as randomized controlled trials should be considered to confirm these findings.

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